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"Human genetics."
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Inheritance : how our genes change our lives--and our lives change our genes
Explains new concepts in human genetics and health that indicate that the fundamental nature of the human genome is much more fluid and flexible than originally thought.
BOOK
Genetic mechanisms of critical illness in COVID-19
Host-mediated lung inflammation is present
1
, and drives mortality
2
, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development
3
. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079,
P
= 1.65 × 10
−8
) in a gene cluster that encodes antiviral restriction enzyme activators (
OAS1
,
OAS2
and
OAS3
); on chromosome 19p13.2 (rs74956615,
P
= 2.3 × 10
−8
) near the gene that encodes tyrosine kinase 2 (
TYK2
); on chromosome 19p13.3 (rs2109069,
P
= 3.98 × 10
−12
) within the gene that encodes dipeptidyl peptidase 9 (
DPP9
); and on chromosome 21q22.1 (rs2236757,
P
= 4.99 × 10
−8
) in the interferon receptor gene
IFNAR2
. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of
IFNAR2
, or high expression of
TYK2
, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte–macrophage chemotactic receptor
CCR2
is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice.
A genome-wide association study of critically ill patients with COVID-19 identifies genetic signals that relate to important host antiviral defence mechanisms and mediators of inflammatory organ damage that may be targeted by repurposing drug treatments.
Journal Article
Reproduction and genetics
Reviews the fundamental concepts of reproduction and how genetic information determines the physical characteristics of an organism.
Book
A high-resolution HLA reference panel capturing global population diversity enables multi-ancestry fine-mapping in HIV host response
Fine-mapping to plausible causal variation may be more effective in multi-ancestry cohorts, particularly in the MHC, which has population-specific structure. To enable such studies, we constructed a large (
n
= 21,546) HLA reference panel spanning five global populations based on whole-genome sequences. Despite population-specific long-range haplotypes, we demonstrated accurate imputation at G-group resolution (94.2%, 93.7%, 97.8% and 93.7% in admixed African (AA), East Asian (EAS), European (EUR) and Latino (LAT) populations). Applying HLA imputation to genome-wide association study data for HIV-1 viral load in three populations (EUR, AA and LAT), we obviated effects of previously reported associations from population-specific HIV studies and discovered a novel association at position 156 in HLA-B. We pinpointed the MHC association to three amino acid positions (97, 67 and 156) marking three consecutive pockets (C, B and D) within the HLA-B peptide-binding groove, explaining 12.9% of trait variance.
A high-resolution reference panel based on whole-genome sequencing data enables accurate imputation of
HLA
alleles across diverse populations and fine-mapping of HLA association signals for HIV-1 host response.
Journal Article
Reflections of our past : how human history is revealed in our genes
'Reflections Of Our Past' provides an accessible examination of how the genes of living people reveal the history of humankind, from the origins of humans 6 million years ago up to the present.
Opportunistic genomic screening. Recommendations of the European Society of Human Genetics
If genome sequencing is performed in health care, in theory the opportunity arises to take a further look at the data: opportunistic genomic screening (OGS). The European Society of Human Genetics (ESHG) in 2013 recommended that genome analysis should be restricted to the original health problem at least for the time being. Other organizations have argued that ‘actionable’ genetic variants should or could be reported (including American College of Medical Genetics and Genomics, French Society of Predictive and Personalized Medicine, Genomics England). They argue that the opportunity should be used to routinely and systematically look for secondary findings—so-called opportunistic screening. From a normative perspective, the distinguishing characteristic of screening is not so much its context (whether public health or health care), but the lack of an indication for having this specific test or investigation in those to whom screening is offered. Screening entails a more precarious benefits-to-risks balance. The ESHG continues to recommend a cautious approach to opportunistic screening. Proportionality and autonomy must be guaranteed, and in collectively funded health-care systems the potential benefits must be balanced against health care expenditures. With regard to genome sequencing in pediatrics, ESHG argues that it is premature to look for later-onset conditions in children. Counseling should be offered and informed consent is and should be a central ethical norm. Depending on developing evidence on penetrance, actionability, and available resources, OGS pilots may be justified to generate data for a future, informed, comparative analysis of OGS and its main alternatives, such as cascade testing.
Journal Article
Enhancing Evolution
InEnhancing Evolution, leading bioethicist John Harris dismantles objections to genetic engineering, stem-cell research, designer babies, and cloning and makes an ethical case for biotechnology that is both forthright and rigorous. Human enhancement, Harris argues, is a good thing--good morally, good for individuals, good as social policy, and good for a genetic heritage that needs serious improvement.Enhancing Evolutiondefends biotechnological interventions that could allow us to live longer, healthier, and even happier lives by, for example, providing us with immunity from cancer and HIV/AIDS. Further, Harris champions the possibility of influencing the very course of evolution to give us increased mental and physical powers--from reasoning, concentration, and memory to strength, stamina, and reaction speed. Indeed, he says, it's not only morally defensible to enhance ourselves; in some cases, it's morally obligatory.
In a new preface, Harris offers a glimpse at the new science and technology to come, equipping readers with the knowledge to assess the ethics and policy dimensions of future forms of human enhancement.
eBook
Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder
Survey of postzygotic mosaic mutations (PZMs) in 5,947 trios with autism spectrum disorders (ASD) discovers differences in mutational properties between germline mutations and PZMs. Spatiotemporal analyses of the PZMs also revealed the association of the amygdala with ASD and implicated risk genes, including recurrent potential gain-of-function mutations in
SMARCA4
.
We systematically analyzed postzygotic mutations (PZMs) in whole-exome sequences from the largest collection of trios (5,947) with autism spectrum disorder (ASD) available, including 282 unpublished trios, and performed resequencing using multiple independent technologies. We identified 7.5% of
de novo
mutations as PZMs, 83.3% of which were not described in previous studies. Damaging, nonsynonymous PZMs within critical exons of prenatally expressed genes were more common in ASD probands than controls (
P
< 1 × 10
−6
), and genes carrying these PZMs were enriched for expression in the amygdala (
P
= 5.4 × 10
−3
). Two genes (
KLF16
and
MSANTD2
) were significantly enriched for PZMs genome-wide, and other PZMs involved genes (
SCN2A
,
HNRNPU
and
SMARCA4
) whose mutation is known to cause ASD or other neurodevelopmental disorders. PZMs constitute a significant proportion of
de novo
mutations and contribute importantly to ASD risk.
Journal Article